Abstract | BACKGROUND: Previous studies suggested involvement of non-ß- adrenoceptors in the pathogenesis of Takotsubo cardiomyopathy (TTC). This study was designed to explore possible roles and underlying mechanisms of dopamine D1/D5 receptor coupled signaling in arrhythmogenesis of TTC. METHODS: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were challenged by toxic concentration of epinephrine (Epi, 0.5 mM for 1 h) for mimicking the catecholamine excess in setting of TTC. Specific receptor blockers and activators were used to unveil roles of D1/D5 receptors. Patch clamp, qPCR, and FACS analyses were performed in the study. RESULTS: High concentration Epi and two dopamine D1/D5 receptor agonists [(±)- SKF 38393 and fenoldopam] reduced the depolarization velocity and prolonged the duration of action potentials (APs) and caused arrhythmic events in iPSC-CMs, suggesting involvement of dopamine D1/D5 receptor signaling in arrhythmogenesis associated with QT interval prolongation in the setting of TTC. (±)- SKF 38393 and fenoldopam enhanced the reactive oxygen species (ROS)-production. H2O2 (100 μM) recapitulated the effects of (±)- SKF 38393 and fenoldopam on APs and a ROS-blocker N-acetylcysteine (NAC, 1 mM) abolished the effects, suggesting that the ROS-signaling is involved in the dopamine D1/D5 receptor actions. A NADPH oxidases blocker and a PKA- or PKC-blocker suppressed the effects of the dopamine receptor agonist, implying that PKA, NADPH oxidases and PKC participated in dopamine D1/D5 receptor signaling. The abnormal APs resulted from dopamine D1/D5 receptor activation-induced dysfunctions of ion channels including the Na+ and L-type Ca2+ and IKr channels. CONCLUSIONS:
Dopamine D1/D5 receptor signaling plays important roles for arrhythmogenesis of TTC. Dopamine D1/D5 receptor signaling in cardiomyocytes might be a potential target for treating arrhythmias in patients with TTC.
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Authors | Mengying Huang, Zhen Yang, Yingrui Li, Huan Lan, Lukas Cyganek, Goekhan Yuecel, Siegfried Lang, Karen Bieback, Ibrahim El-Battrawy, Xiaobo Zhou, Martin Borggrefe, Ibrahim Akin |
Journal | Frontiers in cardiovascular medicine
(Front Cardiovasc Med)
Vol. 8
Pg. 777463
( 2021)
ISSN: 2297-055X [Print] Switzerland |
PMID | 35187102
(Publication Type: Journal Article)
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Copyright | Copyright © 2022 Huang, Yang, Li, Lan, Cyganek, Yuecel, Lang, Bieback, El-Battrawy, Zhou, Borggrefe and Akin. |